In 1881, Talmage received a collegiate diploma from BYA's Scientific Department, the first such diploma to be issued. His early predilection was for the sciences, and in 1882 and 1883 he took selected courses in chemistry and geology at Lehigh University in Bethlehem, Pennsylvania.

Though a special student and not a candidate for a degree, during his single year Talmage passed nearly all the examinations required in the four-year course; he graduated and in 1883 and 1884 he was engaged in advanced work at Johns Hopkins University in Baltimore, Maryland. Talmage served on the Provo City Council in 1888 and 1889.[1]

Talmage married Merry May Booth (1868–1944) on June 14, 1888. Booth was a native of Alpine, Utah, and the daughter of immigrants from Lancashire.[2] She started studies at the normal school connected with BYA in 1885, when she was 16. It was there she met Talmage, who was one of her instructors. While at BYA, Booth was secretary of the Polysophical Society. After completing her course of normal study, May took a job as a teacher in Kaysville, Utah. A few months later, Talmage undertook a project to study the waters of the Great Salt Lake; Talmage's main reason for this journey, though, was to pursue a relationship with Booth, and five months later they were married.

The Talmages had eight children. Among their children was John Talmage, who wrote a biography of his father. Another of their children, Sterling B. Talmage (1889–1956), followed his father's interests and became a geologist.[3]

In the spring of 1884, while at Johns Hopkins, Talmage journaled about laboratory experiments involving the ingestion of hashish, reporting that interviews with users conducted by himself and two colleagues yielded very different accounts of the experience.[5] Talmage noted that the ill effects of opium were very unpleasant and had been well-documented, "[b]ut the ill effects are reported very low in the Haschich or Hemp administration; and we have concluded to try effect of a small dose upon ourselves ... though I very much dislike the idea of doing such a thing, for as yet I have never known what it is to be narcotized either by tobacco, alcohol, or any drug."[5] Thus, on three occasions, March 22, April 5, and April 6, 1884, Talmage ingested increasing doses; on the first two occasions he felt no effect, but on the third he reported simply, "[c]ontinued my experiment by taking 20 grains Cannabis Indica and the effect was felt in a not very agreeable way."[5]

Talmage taught science at BYA both before and after he went to study in the eastern United States. He was the president of Latter-day Saints' University until 1894 and then was president of the University of Deseret from 1894 to 1897.[6] From 1897 to 1907, Talmage was a professor of geology at the University of Utah.

In 1909, Talmage was serving as the director of the Deseret Museum. He went to Detroit, Michigan, in November of that year to participate in diggings connected with the Scotford-Soper-Savage relics craze.[7] Talmage would go on to denounce these findings as a forgery in the September 1911 edition of the Deseret Museum Bulletin in an article entitled, "The Michigan Relics: A Story of Forgery and Deception".

In 1911, the church's First Presidency learned that a photographer had gained unauthorized access to the Salt Lake Temple, had taken numerous photographs of the interior, and was holding those photographs for ransom. Talmage suggested that the First Presidency commission its own photographs of the temple. Church president Joseph F. Smith authorized Talmage to write an apology on the subject of the temple to accompany the publication of the photographs. Shortly thereafter, The House of the Lord was published.[8][9]